Mir-144 selectively regulates embryonic alpha-hemoglobin synthesis during primitive erythropoiesis.
Precise transcriptional control of developmental stage-specific expression and switching of alpha- and beta-globin genes is significantly important to understand the general principles controlling gene expression and the pathogenesis of thalassemia. Although transcription factors regulating beta-globin genes have been identified, little is known about the microRNAs and trans-acting mechanism controlling alpha-globin genes transcription. Here, we show that an erythroid lineage-specific microRNA gene, miR-144, expressed at specific developmental stages during zebrafish embryogenesis, negatively regulates the embryonic alpha-globin, but not embryonic beta-globin, gene expression, through physiologically targeting klfd, an erythroid-specific Krüppel-like transcription factor. Klfd selectively binds to the CACCC boxes in the promoters of both alpha-globin and miR-144 genes to activate their transcriptions, thus forming a negative feedback circuitry to fine-tune the expression of embryonic alpha-globin gene. The selective effect of the miR-144-Klfd pathway on globin gene regulation may thereby constitute a novel therapeutic target for improving the clinical outcome of patients with thalassemia.
Fu
Yan-Fang
YF
Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Du
Ting-Ting
TT
Dong
Mei
M
Zhu
Kang-Yong
KY
Jing
Chang-Bin
CB
Zhang
Yong
Y
Wang
Lei
L
Fan
Hong-Bo
HB
Chen
Yi
Y
Jin
Yi
Y
Yue
Gui-Ping
GP
Chen
Sai-Juan
SJ
Chen
Zhu
Z
Huang
Qiu-Hua
QH
Jing
Qing
Q
Deng
Min
M
Liu
Ting Xi
TX
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D019295:Computational Biology; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism*; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D055542:alpha-Globins / Q000235:genetics* / Q000378:metabolism; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism
D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; D009841:Oligonucleotides; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D055542:alpha-Globins; D055544:beta-Globins; C485184:enhanced green fluorescent protein; C436493:klf1 protein, zebrafish; C477371:locked nucleic acid; D049452:Green Fluorescent Proteins